Sleep is present in all species where it has been studied, but its functions remain unknown. A sufficient amount of sleep constitutes a fundamental biological need. For example, curtailing the amount of sleep in normal sleepers affects performance, vigilance, memory and health. Like all complex behaviors, sleep is both environmentally modulated and genetically determined. However, the responsible genes have not been discovered. To identify them, we have initiated a genetic screening for short sleepers in the fruit fly Drosophila melanogaster. Mutagenesis screening in Drosophila has helped unraveling cellular mechanisms that are highly conserved across species, e.g. those controlling development, aging, stress memory, and circadian rhythms. Over the past few years, our laboratory and others have shown that fly sleep shares many key features with mammalian sleep. As in mammals, sleep in Drosophila is characterized by increased arousal thresholds and by changes in brain electrical activity. Fly sleep is regulated independent of the circadian clock, is modulated by stimulants and hypnotics, and is affected by age. Also, fly sleep is associated with changes in brain gene expression similar to those observed in mammals. Over the past 3 years, we have screened approximately 8000 mutant lines, most of which carry single-gene mutations. We found that the amount and regulation of sleep are highly conserved: almost all flies sleep between 400 and 800 min/24 hours and show increased sleep duration and continuity after sleep deprivation. We have also identified several short sleeper lines, three of which are particularly interesting. Despite the reduced amount of sleep (<230 min/day), these lines show normal day-time performance and vigilance. When sleep deprived, they recover most of the sleep lost, suggesting that it is biologically important. The short sleep mutation is due to the genomic insertion of a P element whose mobilization reverts them to normal sleep, suggesting a single gene effect. We propose to characterize these three lines genetically, molecularly, and behaviorally. We will manipulate the expression of the genes responsible for the short sleep phenotype, investigate the molecular pathways controlled by these genes, and characterize their impact on performance, memory, circadian rhythms and life span. This research will help to identify the molecular mechanisms regulating the need for sleep and provide novel clues to its functions.